Esophageal adverse experiences, such as esophagitis,
esophageal ulcers and esophageal erosions, occasionally with bleeding and
rarely followed by esophageal stricture or perforation, have been reported in
patients receiving treatment with oral bisphosphonates. In some cases, these
have been severe and required hospitalization. Physicians should therefore be
alert to any signs or symptoms signaling a possible esophageal reaction and
patients should be instructed to discontinue Atelvia and seek medical attention
if they develop dysphagia, odynophagia, retrosternal pain or new or worsening
heartburn.

The risk of severe esophageal adverse experiences appears
to be greater in patients who lie down after taking oral bisphosphonates and/or
who fail to swallow it with the recommended 4 ounces of water, and/or who
continue to take oral bisphosphonates after developing symptoms suggestive of
esophageal irritation. Therefore, it is very important that the full dosing
instructions are provided to, and understood by, the patient [see DOSAGE AND
ADMINISTRATION]. In patients who cannot comply with dosing instructions due
to mental disability, therapy with Atelvia should be used under appropriate
supervision.

There have been post-marketing reports of gastric and
duodenal ulcers with oral bisphosphonate use, some severe and with
complications, although no increased risk was observed in controlled clinical
trials.

Mineral Metabolism

Hypocalcemia has been reported in patients taking
Atelvia. Treat hypocalcemia and other disturbances of bone and mineral
metabolism should be effectively treated before starting Atelvia therapy.
Instruct patients to take supplemental calcium and vitamin D if their dietary
intake is inadequate. Adequate intake of calcium and vitamin D is important in
all patients [seeCONTRAINDICATIONS, ADVERSE REACTIONS, PATIENT INFORMATION].

For patients requiring invasive dental procedures,
discontinuation of bisphosphonate treatment may reduce the risk for ONJ.
Clinical judgment of the treating physician and/or oral surgeon should guide
the management plan of each patient based on individual benefit/risk
assessment.

Patients who develop ONJ while on bisphosphonate therapy
should receive care by an oral surgeon. In these patients, extensive dental
surgery to treat ONJ may exacerbate the condition. Discontinuation of
bisphosphonate therapy should be considered based on individual benefit/risk
assessment [seeADVERSE REACTIONS].

Musculoskeletal Pain

In postmarketing experience, there have been reports of
severe and occasionally incapacitating bone, joint, and/or muscle pain in
patients taking bisphosphonates [seeADVERSE REACTIONS]. The time to
onset of symptoms varied from one day to several months after starting the
drug. Most patients had relief of symptoms after stopping medication. A subset
had recurrence of symptoms when rechallenged with the same drug or another
bisphosphonate. Consider discontinuing use if severe symptoms develop.

Atypical Subtrochanteric And Diaphyseal Femoral Fractures

Atypical, low-energy, or low trauma fractures of the
femoral shaft have been reported in bisphosphonate-treated patients. These
fractures can occur anywhere in the femoral shaft from just below the lesser
trochanter to above the supracondylar flare and are traverse or short oblique
in orientation without evidence of comminution. Causality has not been
established as these fractures also occur in osteoporotic patients who have not
been treated with bisphosphonates.

Atypical femur fractures most commonly occur with minimal
or no trauma to the affected area. They may be bilateral and many patients
report prodromal pain in the affected area, usually presenting as dull, aching
thigh pain, weeks to months before a complete fracture occurs. A number of
reports note that patients were also receiving treatment with glucocorticoids
(for example, prednisone) at the time of fracture.

Any patient with a history of bisphosphonate exposure who
presents with thigh or groin pain should be suspected of having an atypical
fracture and should be evaluated to rule out an incomplete femur fracture.
Patients presenting with an atypical fracture should also be assessed for symptoms
and signs of fracture in the contralateral limb. Interruption of bisphosphonate
therapy should be considered, pending a risk/benefit assessment, on an
individual basis.

Renal Impairment

Atelvia is not recommended for use in patients with
severe renal impairment (creatinine clearance less than 30 mL/min) because of
lack of clinical experience.

Laboratory Test Interactions

Bisphosphonates are known to interfere with the use of
bone-imaging agents. Specific studies with Atelvia have not been performed.

Patient Counseling Information

Instruct patients to read the
Medication Guide before starting therapy with Atelvia and to re-read it each
time the prescription is renewed.

Instruct patients that Atelvia
and Actonel contain the same active ingredient and if they are taking Actonel,
they should not take Atelvia [see WARNINGS AND PRECAUTIONS].

Instruct patients to pay particular attention to the
dosing instructions as clinical benefits may be compromised by failure to take
the drug according to instructions.

Instruct patients to take Atelvia in the morning, while
in an upright position (sitting or standing) with at least 4 ounces of plain
water immediately following breakfast. Atelvia should not be taken before
breakfast.

Instruct patients to swallow Atelvia tablets whole.
Patients should not chew, cut, or crush the tablet because of a potential for
oropharyngeal irritation, and because the tablet coating is an important part
of the delayed-release formulation. Patients should not lie down for 30 minutes
after taking the medication.

Instruct patients that if they develop symptoms of
esophageal disease (such as difficulty or pain upon swallowing, retrosternal
pain or severe persistent or worsening heartburn) they should consult their
physician before continuing Atelvia [see WARNINGS AND PRECAUTIONS].

If a dose of Atelvia 35 mg once-a-week is missed,
instruct the patient to take one tablet on the morning after they remember and
return to taking one tablet once-a-week, as originally scheduled on their
chosen day. Patients should not take 2 tablets on the same day.

Instruct patients to take supplemental calcium and
vitamin D if dietary intake is inadequate [see WARNINGS AND PRECAUTIONS].

Instruct patients to take calcium supplements, antacids,
magnesium-based supplements or laxatives, and iron preparations at a different
time of the day because they interfere with the absorption of Atelvia.

Remind patients to give all of their healthcare providers
an accurate medication history. Instruct patients to tell all of their
healthcare providers that they are taking Atelvia. Patients should be
instructed that any time they have a medical problem they think may be from
Atelvia they should talk to their doctor.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In a 104-week carcinogenicity study, rats were
administered daily oral doses up to approximately 8 times the human Paget's
disease dose of 30 mg/day. There were no significant drug-induced tumor
findings in male or female rats. The high dose male group was terminated early
in the study (Week 93) due to excessive toxicity, and data from this group were
not included in the statistical evaluation of the study results. In an 80-week
carcinogenicity study, mice were administered daily oral doses approximately
6.5 times the human dose. There were no significant drug-induced tumor findings
in male or female mice.

Mutagenesis

Risedronate did not exhibit genetic toxicity in the
following assays: In vitro bacterial mutagenesis in Salmonella and E.
coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay,
unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal
aberrations in vivo in rat bone marrow. Risedronate was positive in a
chromosomal aberration assay in CHO cells at highly cytotoxic concentrations
(greater than 675 mcg/mL, survival of 6% to 7%). When the assay was repeated at
doses exhibiting appropriate cell survival (29%), there was no evidence of
chromosomal damage.

Impairment of Fertility

In female rats, ovulation was inhibited at an oral dose
approximately 5 times the human dose. Decreased implantation was noted in
female rats treated with doses approximately 2.5 times the human dose. In male
rats, testicular and epididymal atrophy and inflammation were noted at
approximately 13 times the human dose. Testicular atrophy was also noted in
male rats after 13 weeks of treatment at oral doses approximately 5 times the
human dose. There was moderate-tosevere spermatid maturation block after 13 weeks
in male dogs at an oral dose approximately 8 times the human dose. These
findings tended to increase in severity with increased dose and exposure time.

Dosing multiples provided above are based on the
recommended human Paget's disease dose of 30 mg/day and normalized using body
surface area (mg/m²). Actual doses were 24 mg/kg/day in rats, 32
mg/kg/day in mice, and 8, 16 and 40 mg/kg/day in dogs.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of
Atelvia in pregnant women. Atelvia should be used during pregnancy only if the
potential benefit justifies the potential risk to the mother and fetus.

Bisphosphonates are incorporated into the bone matrix,
from which they are gradually released over periods of weeks to years. The
amount of bisphosphonate incorporation into adult bone, and hence, the amount
available for release back into the systemic circulation, is directly related
to the dose and duration of bisphosphonate use. There are no data on fetal risk
in humans. However, there is a theoretical risk of fetal harm, predominantly
skeletal, if a woman becomes pregnant after completing a course of
bisphosphonate therapy. The impact of variables such as time between cessation
of bisphosphonate therapy to conception, the particular bisphosphonate used,
and the route of administration (intravenous versus oral) on this risk has not
been studied.

In animal studies, pregnant rats received risedronate
sodium during organogenesis at doses 1 to 26 times the human Paget's disease
dose of 30 mg/day. Survival of neonates was decreased in rats treated during
gestation with oral doses approximately 5 times the human dose and body weight
was decreased in neonates from dams treated with approximately 26 times the
human dose. The number of fetuses exhibiting incomplete ossification of
sternebrae or skull from dams treated with approximately 2.5 times the human
dose was significantly increased compared to controls. Both incomplete
ossification and unossified sternebrae were increased in rats treated with oral
doses approximately 5 times the human dose. A low incidence of cleft palate was
observed in fetuses from female rats treated with oral doses approximately
equal to the human dose. The relevance of this finding to human use of Atelvia
is unclear.

No significant fetal ossification effects were seen in
rabbits treated with oral doses approximately 7 times the human dose (the
highest dose tested). However, 1 of 14 litters were aborted and 1 of 14 litters
were delivered prematurely.

Similar to other bisphosphonates, treatment during mating
and gestation with doses of risedronate sodium approximately the same as the
human Paget's disease dose of 30 mg/day resulted in periparturient hypocalcemia
and mortality in pregnant rats allowed to deliver.

Dosing multiples provided above are based on the
recommended human Paget's disease dose of 30 mg/day and normalized using body
surface area (mg/m²). Actual animal doses were 3.2, 7.1 and 16
mg/kg/day in the rat and 10 mg/kg/day in the rabbit.

Nursing Mothers

Risedronate was detected in feeding pups exposed to
lactating rats for a 24-hour period post-dosing, indicating a small degree of
lacteal transfer. It is not known whether Atelvia is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants from Atelvia, a decision should be
made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.

Pediatric Use

Atelvia is not indicated for use in pediatric patients.

The safety and effectiveness of risedronate sodium
immediate-release was assessed in a one-year, randomized, double-blind,
placebo-controlled study of 143 pediatric patients (94 received risedronate)
with osteogenesis imperfecta (OI). The enrolled population was predominantly
patients with mild OI (85% Type-I), aged 4 to less than 16 years, 50% male and
82% Caucasian, with a mean lumbar spine BMD Z-score of -2.08 (2.08 standard
deviations below the mean for age-matched controls). Patients received either a
2.5 mg (less than or equal to 30 kg body weight) or 5 mg (greater than 30 kg
body weight) daily oral dose. After one year, an increase in lumbar spine BMD
in the risedronate sodium immediate-release group compared to the placebo group
was observed. However, treatment with risedronate sodium immediate-release did
not result in a reduction in the risk of fracture in pediatric patients with
OI. In risedronate sodium immediate-release treated subjects, no mineralization
defects were noted in paired bone biopsy specimens obtained at baseline and
month 12.

The overall safety profile of risedronate in OI patients
treated for up to 12 months was generally similar to that of adults with
osteoporosis. However, there was an increased incidence of vomiting compared to
placebo. In this study, vomiting was observed in 15% of children treated with
risedronate sodium immediate-release and 6% of patients treated with placebo.
Other adverse reactions reported in greater than or equal to 10% of patients
treated with risedronate sodium immediate-release and with a higher frequency
than placebo were: pain in the extremity (21% with risedronate sodium
immediate-release versus 16% with placebo), headache (20% versus 8%), back pain
(17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%),
and bone pain (10% versus 4%).

Geriatric Use

Of the patients receiving Atelvia in postmenopausal
osteoporosis studies, 59% were 65 and over, while 13% were 75 and over. No
overall differences in safety or effectiveness were observed between these
patients and younger patients, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment

Atelvia is not recommended for use in patients with
severe renal impairment (creatinine clearance less than 30 mL/min) because of
lack of clinical experience. No dosage adjustment is necessary in patients with
a creatinine clearance greater than or equal to 30 mL/min.

Hepatic Impairment

No studies have been performed to assess risedronate
sodium's safety or efficacy in patients with hepatic impairment. Risedronate is
not metabolized in human liver preparations. Dosage adjustment is unlikely to
be needed in patients with hepatic impairment.

Last reviewed on RxList: 4/13/2015
This monograph has been modified to include the generic and brand name in many instances.